Manufacture of pure hydralazine salts

ABSTRACT

The present invention provides an improved process of preparing hydralazine hydrochloride, which involves the preparation of 1-chlorophthalazine salt and further reacting with hydrazine followed by purification of hydralazine hydrochloride, which is free of phosphate, does not contain any individual impurities more than 0.05%, total impurities less than 0.5%, and a hydrazine content of not more than 0.001%, and preferably less than 0.0003%. One benefit of improved purity is enhanced storage stability.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/296,178 filed on Dec. 7, 2005, the content of which is incorporatedherein by reference.

FIELD OF THE INVENTION

This invention relates to methods for making hydralazine and itspurification, including methods for making and purifying intermediatesin the process.

BACKGROUND OF THE INVENTION

Hydralazine (e.g., Apresoline brand) is used to treat arterialhypertension (primary; malignant; pulmonary; pre-eclampsia andeclampsia), congestive heart failure, pulmonary hypertension in chronicobstructive pulmonary disease, and aortic regurgitation (McFadden, E RJr & Braunwald, E., “Cor pulmonale,” p. 1581-1601, Heart Diseases. ATextbook of Cardiovascular-Medicine (4th ed.) (Philadelphia: W BSaunders, 1992); Gallagher, M W; Repke, J T & Goldstein, P J (1994),“Pharmacologic Approach to the Critically Ill Obstetric Patient,” p:847-862, The Pharmacologic Approach to the Critically Ill Patient (3rded.), Chernow, B (ed.) (Oates, I A: Williams & Wilkins, 1995);Antihypertensive Agents and Drug Therapy of Hypertension, Goodman &Gilman's The Pharmacological Basis of Therapeutics (9th ed.), p.809-838, Hardman, Limbird; Molinoff, Ruddon, and Gilman (eds.), (NewYork: McGraw/Hill); Chatterjee et al., Ann. Intern. Merl, Vol. 92, pp.600-604 (1980); and Franciosa et al, Am. Heart .1, Vol. 104, pp. 587594(1982). Some benefit may be seen if used in primary esophageal motilitydisorders (Mellow, M H, “Effect of isosorbide and hydralazine in painfulprimary esophageal motility disorders”, Gastroenterology, 83:364-370(1982)) and psoriasis (Isaac, P., “Hydralazine and psoriasis,” Br. Med.J., 285:744 (1982)). Recent observations indicate hydralazine can beused to withdraw patients from dobutamine in severe congestive heartfailure (Binkley P F., et al., “Usefulness of hydralazine to withdrawfrom dobutamine in severe congestive heart failure,” Am. Cardia,68:1103-1106 (1991)). Infants with chronic heart failure andleft-to-right shunts may experience some benefit with hydralazine use(Artman, M, et al., “Short-term hemodynamic effects of hydralazine ininfants with complete arterioventricular canal defects,” Circulation,69:949-954 (1984)).

Uses of hydralazine along with other drugs have been reported by JayCohn et al. (U.S. Pat. Nos. 4,868,179, 6,784,177, and 6,465,463) fortreating and preventing mortality associated with heart failure,improving oxygen consumption, quality of life and/or exercise tolerancein a black patient with hypertension.

Hydralazine hydrochloride is an artery specific direct peripheralvasodilator drug used to treat essential hypertension and it iscommercially available in both oral and injectable dosage forms in theU.S. and other countries. Hydralazine hydrochloride is a drug having anonset of action with oral administration between 10-30 minutes (10-20minutes given intravenously), a maximum hypotensive effect in 10-80minutes, and duration of action between 3-4 hours.

Despite approval by the U.S. Food and Drug Administration (FDA) foradministration of 20 mg hydralazine hydrochloride injectable doses,several clinical hazards are reported with the currently availablehydralazine injectable formulations. Stability of the sterile injectionsolution is a serious problem due to the formation of particles in thehydralazine sterile injection solutions during storage for more than sixmonths. These stability issues with hydralazine hydrochloride injectablesolutions are likely due to the minor impurities present in the drug.

Donald has described in U.S. Patent Pub. 2003/0212272 that an injectableformulation of hydralazine forms small yellow-green particles followingstorage for one to two months at 40° C., and similarly after storage forsix to nine months at 25° C. Although the identification of theyellow-green particles has yet to be confirmed, it is believed that theparticles are insoluble polymeric products formed during storage ofhydralazine—that the compound undergoes degradation in stored sterileinjectable solutions, forming insoluble polymeric products because ofthe highly reactive hydrazino group. Hydralazine hydrochloride alsoundergoes several pharmaceutically undesirable reactions such aschelation with metal ions, oxidation, and pH-dependent decomposition. Itis believed that these reactions, which often cause discoloration ofhydralazine compositions, are also due to the highly reactive hydrazinogroup. Lessen et al., J. Pharmaceutical Sci., 85(3): 326-329(1996),report that, in addition to the usual hydralazine degradants such asphthalazone and phthalazine, tablet compositions producedtriazolophthalazine derivatives. Sinha and Motten, in Biochemical andBiophysical Research Communications 105(3). 1044-1051 (1982), reportthat hydralazine oxidizes rapidly in the presence of oxygen and metalcompounds such as Cu⁺², Fe⁺², and Fe⁺³ through free radicalintermediates, much like other hydrazine derivatives.

As described in the art, the hydralazine drug molecule is sensitive toexcipients reactive with its hydrazine moiety. In addition toexcipients, impurities present in the drug substance play a key role incausing instability of sensitive molecules such as hydralazine. Thermaldegradation and hydrolysis of hydralazine gives phthalazinone,phthalazine, and triazolophthalazine. Producing hydralazinehydrochloride in significantly purer form would significantly improvethe stability of the product and thus maintain its safety and efficacy.

The first process of preparing hydralazine (1-hydrazinophthalazine) andits salts was reported in U.S. Pat. No. 2,484,029 and British Pat. No.629,177. This process involved the preparation of 1-chlorophthalazine(from phthalazinone by the process reported in Ber. D. deutsch. chem.Ges., Vol., 26, page 521 (1893)), and the freshly obtained yet moistchloro compound was further reacted with a mixture of 100 parts byvolume of ethyl alcohol and 90 parts by volume of hydrazine hydrate. Thehydralazine thus obtained was recrystallized from methanol and convertedto the hydrochloride salt on warming in alcoholic or aqueoushydrochloric acid. Hydralazine hydrochloride obtained by this process isfound to contain several impurities at about 0.5%, has a greater than0.01% level of hydrazine content, and does not comply with the presentpharmacopoeial requirements for the drug. The U.S. Pharmacopoeiarequires the hydralazine drug substance to be free of hydrazine at alevel less than 0.001%, and the European Pharmacopoeia requires anyindividual impurities to be present at levels not more than 0.2%.

More recently, U.S. Patent Pub. 2005/0137397 (the '397 application)discloses the process of preparing hydralazine hydrochloride involvingthe preparation of chlorophthalazine from phthalazinone and phosphorousoxychloride, separating using a first solvent such as an alkane having 5to 7 carbons and a second solvent (such as tetrahydrofuran), reactingthe isolated chlorophthalazine with hydrazine in presence of alcohol toproduce hydralazine, and treating the hydralazine with hydrochloric acidto yield hydralazine hydrochloride. It is disclosed that the producthydralazine hydrochloride obtained by this process contains phthalazineimpurities less than 0.5% and hydrazine content less than 0.0005%.

The process of the '397 application has a number of drawbacks. Thechlorophthalazine prepared as disclosed in this publication was found tocontain more insoluble matter. In addition, the process of isolatingchlorophthalazine, as disclosed in this publication, involves decantinga supernatant liquid mixture containing several volumes of hexane andphosphorous oxychloride, a cumbersome operation and that is a seriouslimitation towards scaling-up the disclosed process. The description inthe '397 application of the hydralazine hydrochloride produced is paleyellow in color, and off-white after recrystallization from ethanol.

There is no reported procedure in the art for the purification ofhydralazine to remove the yellow color and for the reduction ofhydrazine content to a level of below 0.001%.

Hydralazine hydrochloride is one of the drugs known for its instabilityin injectable solution during storage. This problem calls for the needof a process to produce hydralazine hydrochloride free of significantlevel of impurities and for the need of a process of purification ofimpure hydralazine hydrochloride

SUMMARY OF THE INVENTION

It is a prime object of this invention to provide a commercially viablemanufacturing process for preparing hydralazine hydrochloride insignificantly purer form containing any individual impurity not morethan 0.05%, total impurities less than 0.5%, and a hydrazine content notmore than (NMT) 0.001%.

The present invention describes a novel process of producing purehydralazine useful for, among other conditions, the treatment ofhypertension and related heart diseases.

The present invention provides a number of novel improvements thatprovide a safer and simpler routes or subprocesses to intermediatesuseful in the production of hydralazine, and ultimately allow productionof pure hydralazine salts, with fewer impurities.

Another important aspect of this invention is to provide a novel processfor purifying hydralazine hydrochloride by using an aqueous medium toremove the yellow coloration and to reduce hydrazine content to a levelbelow 0.001%.

Yet another novel aspect of the process of this invention is theisolation of chlorophthalazine as a mineral acid salt or salt mixture,without distillation or the need to concentrate the reaction mass. Thisnovel process of isolation is commercially viable and can be scaled upto production level. In addition, the amount of phosphorous oxychlorideused is less than 1 mol equivalent to phthalazinone, providing lowexothermicity and therefore a safer process, especially when scaled-up;the prior art has always suggested use of phosphorous oxychloride atmuch higher level of about 4 mol equivalent. The additional purificationprocess of treating hydralazine solution with activated carbon andchelating agents allows removal of yellow color of the material.

In summary, one embodiment of this invention provides a novel improvedprocess of: a) reacting phthalazinone with about one mole equivalent ofphosphorus oxychloride and then acidifying the medium to produce a1-chlorophthalazine salt optionally in admixture with a mineral acid; b)reacting the product of step (a) with hydrazine in an aqueous oralcoholic, and otherwise essentially non-organic, medium to producehydralazine base; and c) converting the hydralazine base to hydralazinehydrochloride. Further, the present invention provides a novel improvedprocess of purification of the hydralazine hydrochloride, which can beperformed by dissolution in aqueous medium followed by treatment with anadsorbent and/or chelating agent, removal of the same, and precipitationof the final product by cooling.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a number of novel process steps andcombinations thereof in the preparation of hydralazine, includingobtaining pure chlorophthalazine salt by a precipitation process,forming hydralazine base in the absence of an organic solvent, and anovel process of purifying hydralazine hydrochloride.

The process according to one embodiment of this invention comprises thesteps of: a) reacting phthalazinone with an approximately equimolarequivalent of phosphorous oxychloride at a specific temperature toproduce a 1-chlorophthalazine salt; b) isolating the 1-chlorophthalazinesalt formed in step (a) by precipitating the 1-chlorophthalazine salt byadding a mineral acid in the presence of solvent and filtering anddrying the solid 1-chlorophthalazine salt; c) reacting the isolated anddried 1-chlorophthalazine salt with hydrazine hydrate without anyorganic solvent and precipitating the hydralazine base by adding asolvent; d) purifying the hydralazine base in a non-aqueous medium; e)converting the purified hydralazine base to hydralazine hydrochloride ina non-aqueous medium and isolating therein; and f) purifying theisolated hydralazine hydrochloride in aqueous medium

According to another embodiment, this invention provides a process forpurifying hydralazine hydrochloride comprising the steps of: a)dissolving hydralazine hydrochloride in hot water; b) treating thesolution with color adsorbent and a chelating agent; c) filtering offthe adsorbent and chelating agent; d) adjusting the pH of the mixture;and e) precipitating hydralazine hydrochloride by adding a watermiscible solvent at a lower temperature.

In one preferred embodiment of the process of this invention,phthalazinone was reacted with phosphorous oxychloride in toluene at atemperature of about 45° C. to about 65° C. for about 3 hours. Ethylacetate and sulfuric acid were added to complete the precipitation ofthe 1-chlorophthalazine salt. The product 1-chlorophthalazinonehydrochloride/sulfate salt produced as such was significantly free ofchlorophosphorylphthalazine.

In another preferred embodiment of this invention, pure hydralazine basewas prepared by the reaction of 1-chlorophthalazinehydrochloride/sulfatesalt with an excess of hydrazine hydrate at a predetermined temperature(preferably between 0° and about 30° C.) without the presence of anorganic solvent during the reaction. After completion of the reaction(which can be monitored by HPLC analysis), the hydralazine base wasprecipitated by adding methanol to the reaction mixture. Alternatively,the reaction can be conducted in the presence of a short-chain aliphaticalcohol, preferably having one to four carbon atoms, but is otherwiseessentially free from organic solvents. As used in connection with themedium in which hydrazine is used to produce hydralazine, “consistingessentially of a non-organic medium” and terms to that effect areintended to include aliphatic alcohols and to exclude aryl compounds andlonger chain alcohols.

The hydralazine base obtained by the process of this invention was paleyellow in color. It was purified by using activated carbon treatment inmethanol and then purified and recovered while in methanol by purgingthe solution with hydrochloric acid gas to precipitate hydralazinehydrochloride. The hydralazine hydrochloride isolated by filtration wasfurther purified by dissolving the crude hydrochloride in hot water inthe presence of activated carbon and a chelating agent such as EDTA. Thecarbon and EDTA suspension were then filtered off from the hot solution,adjusting the pH of the mixture using an acid or base and the purehydralazine hydrochloride was obtained by cooling the pH adjustedmixture followed by precipitating by the addition of methanol.

In another major embodiment of this invention, a process of preparingpure hydralazine hydrochloride is disclosed, comprising the steps of: a)reacting phthalazinone with phosphorous oxychloride at a specifictemperature to produce 1-chlorophthalazine salt; b) concentrating thereaction mixture by distillation; c) isolating the 1-chlorophthalazinesalt concentrated in step (b) by precipitating 1-chlorophthalazine saltthrough the addition of a mineral add in the presence of a solvent,filtering the resulting solid precipitated 1-chtorophthalazine salt, anddrying; d) reacting the isolated and dried 1-chlorophthalazine salt withhydrazine hydrate without any substantial amount of organic solventpresent and precipitating the resulting hydralazine base by adding asolvent; e) purifying the hydralazine base in a non-aqueous medium; f)converting the purified hydralazine base to hydralazine hydrochloride ina non-aqueous medium, and isolating the same; and g) purifying theisolated hydralazine hydrochloride by dissolving hydralazinehydrochloride in hot water to make a solution, treating the solutionwith a color adsorbent and a chelating agent, filtering off theadsorbent and chelating agent, adjusting the pH of the solution using abase or acid, and precipitating hydralazine hydrochloride by adding awater miscible solvent at a lower temperature.

In one preferred embodiment of the process of this invention,phthalazinone was reacted with phosphorous oxychloride at a temperatureof about 45° C. to about 65° C. for about 3 hours. The reaction mass wasconcentrated by distilling out about 65% of the phosphorous oxychlorideunder vacuum (about 600 to 700 mm of mercury) and at an elevatedtemperature (about 45° to about 55 ° C.). To the concentrated reactionmass a predetermined quantity of concentrated sulfuric acid was added ata controlled temperature followed by the addition of ethyl acetate toprecipitate the 1-chlorohydrochloride/sulfate mixture. The product1-chlorophthalazinone hydrochloride/sulfate salt produced as such wassignificantly free of chlorophosphorylphthalazine.

It is preferred that phthalazinone and phosphorous oxychloride arepresent in an approximately molar ratio of less than 1:4, respectively,more preferably not more than about 1:3, more preferably not more thanabout 1:2, and most preferably about 1:1. A reduction in the presence ofthe phosphorous oxychloride means the reaction is less exothermic andthus safer, and more amenable to scaling-up.

The mineral acid used to isolate a 1-chlorophthalazine can be anymineral acid suitable for forming a desired salt, such as a chloride orsulfate; hydrochloric and sulfuric acids, and mixtures thereof, arepreferred.

In the preparation of 1-chlorophthalazine, the solvent used is anorganic solvent, such as toluene, ethyl acetate, or tetrahydrofuran; anysuitable solvent can be used. Preferred are non-polar and slightly polarsolvents like methyl acetate and ethyl acetate, and similar solvents. Onthe other hand, in the reaction with hydrazine hydrate, in which themedium contains essentially no organic solvent, the product is recoveredusing an organic solvent, preferably an aliphatic alcohol (such asmethanol, ethanol, isopropanol, or a combination thereof). In theconversion from hydralazine base to hydralazine hydrochloride, theorganic solvent can be an aliphatic alcohol, tetrahydrofuran, and thelike. In the purification process in which the pH is adjusted, prior toprecipitation, the pH adjustment is preferably done by using a base. Thebase is preferably a mono-, di-, or trialkylamine, arylamine, or aralkylamine, or a sodium base, or a compatible mixture thereof. Examples ofsuitable bases include diethylamine, triethylamine, sodium hydroxide,sodium bicarbonate, sodium carbonate, diisopropylethylamine,isopropyldiethylamine, and the like.

In the purification process using a chelating agent, preferred chelatingagents are organic and include those with at least one carboxyl group,such as ethylenediaminetetraacetic acid (EDTA), ethyleneglycol-his-(13-amino-ethylether)-N,N,N′,N′-tetraacetic acid (EGTA), andcyclohexane-1,2-diaminetetraacetic acid (CDTA).

Further details of this invention are shown in the following examples,which should be taken as descriptive and illustrative of aspects of theinvention and not limiting the scope of the invention.

EXAMPLE 1 (COMPARATIVE)

Preparation of 1-chlorophthalazine

According to the process disclosed in U.S. Patent Pub. 20050137397, thedisclosure of which is incorporated herein by reference, one moleequivalent (250 g) of 1 (2H)-phthalazinone and 3.8 mole equivalents (775g) of phosphorus oxychloride were charged into a 3-L, 3-necked flaskfitted with a temperature probe and condenser. The slurry was stirredand heated to 80° C., maintained at that temperature for 30 minutes, andthen the heat source was removed. The mixture was allowed to cool toroom temperature and 1.6 L of hexane were added. The resulting slurrywas stirred for about 30 minutes, allowed to settle, and the hexanelayer was decanted; the addition of hexane and decantation was repeatedthree times. Then 1.6 L of tetrahydrofuran was added to the slurry and ayellow precipitate formed. The yellow solid (reported in the '397application as an off white solid) was isolated by filtration and thenwashed with 250 mL of cold tetrahydrofuran to afford a 50% yield(reported yield in the '397 application is 85 to 100%) of 1-chlorophthalazine.

EXAMPLE 2 (COMPARATIVE)

Preparation of Hydralazine

Again according to the disclosure in the '397 application, to a 2-L,3-necked, round-bottomed flask fitted with a temperature probe andcondenser were charged 700 mL of ethanol and 7.6 mole equivalents (630mL) of hydrazine hydrate, and the solution was cooled to 50° C. (the'397 application discloses a temperature <10° C.). One (1) moleequivalent (280 g) of 1-chlorophthalazine (solid) was added in portionsat a rate to maintain the solution temperature at <20° C. The solutionwas stirred and heated to 60-70° C. After one hour at that elevatedtemperature, the hot solution was filtered to remove any insolubleby-products (insoluble matter recovered was 12 g), and the filtrate wascooled to 0 to 5° C. A light yellow solid formed in the cold solution,which was isolated by filtration, washed with cold ethanol, and thendried to constant mass and characterized. The yield was 80% (the yieldreported in the '397 application was 77-80%).

EXAMPLE 3 (COMPARATIVE)

Preparation of Hydralazine Hydrochloride

Again according to the disclosure in the '397 application, hydralazinefree base 25 g (1 part by weight) was heated in 165 mL (6 to 7 parts byvolume) of 15% hydrochloric acid to a temperature of 70-80° C. Thesolution was filtered hot to remove traces of insoluble materials thatwere undesired by-products of the preceding step. One hundred sixty fivemilliliters of ethanol (6 to 7 parts by volume) was added to thefiltrate. As the resulting solution cooled to 25° C. (ambienttemperature) and then further cooled to 3-8° C., a pale yellowprecipitate of the desired product, hydralazine hydrochloride,solidified. The obtained yield is 65% (the reported yields in the '397application were 80-90%).

EXAMPLE 4 (COMPARATIVE)

Recrystallization of Hydralazine Hydrochloride

Again according to the '397 application, a single necked, round-bottomedflask was charged with 10 g (1 part by weight of hydralazinehydrochloride) (from Example 3) and 60 mL (6 parts by volume) of 1%hydrochloric acid. The solution was stirred and heated to dissolve thesolid, and then filtered hot, if necessary, to remove traces of coloredinsoluble by-products. Sixty milliliters of ethanol (6 parts by volume)was added to the hot (filtered) solution. As the resulting solutioncooled, a pale yellow precipitate (reported in the '397 application asan off-white precipitate) of purified hydralazine hydrochloride formed.The recrystallized, product was isolated by filtration and washed withfresh, cold ethanol. The isolated material was analyzed for impuritiesand hydrazine content with the following results: hydrazinecontent=0.0004%; yield 90% (reported yield in the '397 application is 85to 100%).

EXAMPLE 5A

Preparation of 1-chlorophthalazine Hydrochloride and Sulfate Mixture

A 3-neck 2 L round-bottomed flask was charged with 584 mL of phosphorousoxychloride (306 g, 2 mol. eq.) and cooled to about 0 to 5° C. To thiswas added 73 g (0.5 mol eq.) of powdered phthalazinone(1-2H-phthalazinone). The reaction mass appeared as a suspension and wasstirred at about 60° C. for about 1 hour. The progress of the reactionwas monitored by HPLC. The reaction mixture was maintained at about 50°C. and about 65% of the phosphorous oxychloride was distilled out undervacuum at that thereby concentrating the solution. The resultingconcentrated reaction mixture was cooled to room temperature and about375 mL of ethyl acetate were added with stirring and cooling to about 0to 5° C. The resulting pale yellow material was filtered and washed with150 mL of ethyl acetate, and the washing was combined with the motherliquor. To the mother liquor was added 12 mL of concentrated sulfuricacid with stirring at 0 to 5° C. for about one hour. The resultingprecipitated 1-chlorophthalazine sulfate was filtered and washed withcold ethyl acetate. The isolated 1-chlorophthalazine salts combined anddried under vacuum for about 3 hours at 30° C. Yield=65%; purity=99%.

EXAMPLE 5B

Preparation of 1-chlorophthalazine Hydrochloride and Sulfate Mixture

A 3-neck 2 L round-bottomed flask was charged with phosphorousoxychloride (306g, 2 mol. eq.) and cooled to about 0 to 5° C. To thisadded 73 g of powdered phthalazinone (0.5 mol eq.) The reaction massappear as a suspension and was stirred at about 60° C. for about 3hours. The progress of the reaction was monitored by HPLC. While thereaction mixture was maintained at 50°-60° C., about 65% of thephosphorous oxychloride was distilled out under vacuum. The concentratedreaction mixture was cooled to room temperature and about 375 mL ofEthyl acetate and 12 mL of concentrated sulfuric acid were added, themixture then stirred for about 1 hour while cooled to 0 to 5° C. Theresulting pale yellow material was filtered and washed with 150 mL ofcold ethyl acetate. The isolated material was 1-chlorophthalazine saltmixture, which was then dried under vacuum for about 3 hours at 30° C.Yield=65%; purity=99%.

EXAMPLE 5C

Preparation of 1-chlorophthalazine Hydrochloride and Sulfate Mixture

A 3-neck 2 L round-bottomed flask was charged with 300 mL toluene and146 g (1 mol eq.) of phthalazinone. Added slowly dropwise to the flaskwas 146 mL of phosphorous oxychloride (1.5 mol. eq.) at roomtemperature. The temperature shot up to about 45° C. The reaction masswas heated to about 60° C. and maintained at a temperature between 60 to65° C. for about 3 hours. The progress of the reaction was monitored byHPLC. After completion, the reaction mixture was cooled to about 5° C.and the precipitation of 1-chlorophthalazine appears. Thereafter wereadded about 800 mL ethylacetate and 24 mL of concentrated sulfuric acidwith stirring for about an hour. The precipitated 1-chlorophthalazinesalt was filtered, washed with acetone and dried under vacuum for about5 hours at 45° C. Yield=85%; purity=99%.

EXAMPLE 5D

Preparation of 1-chlorophthalazine Hydrochloride and Sulfate Mixture

A 3-neck 2 L round-bottomed flask was charged with 300 mL toluene and146 g (1 mol eq.) of phthalazinone. Slowly added dropwise was 292 mL ofphosphorous oxychloride (3.0 mol. eq.) at room temperature. Thetemperature shot up to about 45° C. The reaction mass was heated toabout 60° C. and maintained at a temperature between 60 to 65° C. forabout 3 hours. The progress of the reaction was monitored by HPLC. Thereaction mixture was cooled to about 5° C., after which about 800 mL ofethylacetate and 24 mL of concentrated sulfuric acid was added withstirring for about an hour. The precipitated 1-chlorophthalazine saltwas filtered, washed with acetone and dried under vacuum for about 5hours at 45° C. Yield=70%; purity=99%; the ratio of 1-chlorophthalazinehydrogen sulfate to 1-chlorophthalazine hydrochloride was about 3:2 byweight.

EXAMPLE 6

Preparation of 1-chlorophthalazine Hydrochloride

A 3-neck 2 L round-bottomed flask was charged with phosphorousoxychloride (306 g, 2 mol. eq.) and cooled to about 0 to 5° C. To thiswas added 73 g of powdered phthalazinone (0.5 mol eq.). The reactionmass appeared as a suspension and was heated to about 60° C. withstirring. The progress of the reaction was monitored by HPLC. While thereaction mixture was maintained at approximately 50° C., about 65% ofthe phosphorous oxychloride was distilled out under vacuum. Theconcentrated reaction mixture was cooled to room temperature, about 375mL of ethyl acetate was added, and then the mixture was purged with HClgas for about 30 min; thereafter, the mixture was cooled to atemperature of 0 to 5° C. and stirred for about one hour. The resultingpale yellow material was filtered and washed with 150 mL of cold ethylacetate. The isolated material was 1-chlorophthalazine hydrochloride,which was dried under vacuum for about 3 hours at 30° C. Yield=65%;purity=99%.

EXAMPLE 7A

Preparation of Hydralazine Base in the Absence of Organic Solvent

A 2 L, 3-necked, round-bottomed flask fitted with a temperature probeand condenser, and was charged 375 mL of hydrazine hydrate; the solutionwas then cooled to 0 to 5° C. About 75 g of 1-chlorophthalazine salt wasadded in portions at a rate to maintain the solution temperature at 0 to5° C. After addition, the solution was stirred at 20 to 25° C. for about24 hours. The reaction mixture was then cooled to 0 to 5° C. and 150 mLof methanol was added, the solution stirred for 3 hours, and theresulting solid material was filtered, washed with 150 mL of coldmethanol, and dried under vacuum at 35° C. Yield=99%.

EXAMPLE 7B

Preparation of Hydralazine Base Using Isopropanol

A 500 mL, 3-necked, round-bottom flask fitted with a temperature probeand condenser was charged with 45 mL of hydrazine hydrate and 25 mL ofisopropanol; the solution was cooled to 0 to 5° C. About 9 g of1-chlorophthalazine salt were added in portions at a rate to maintainthe solution temperature at 0 to 5 degrees. The solution was stirred at20 to 25° C. for about 24 hours. The reaction mixture was then cooled to0 to 5° C. and stirred for 3 hours. The resulting solid material wasfiltered from the solution, washed with 15 mL of cold isopropanol, anddried under vacuum at 35° C. Yield=86%.

EXAMPLE 7C

Preparation of Hydralazine Base Using Ethanol

A 500 mL, 3-necked, round-bottom flask fitted with a temperature probeand condenser was charged with 45 mL of hydrazine hydrate; 25 mL ofethanol, and the solution was cooled to 0 to 5° C. About 9 g of 1-chlorophthalazine salt was added in portions at a rate to maintain thesolution temperature at 0 to 5 degrees. The solution was stirred at 20to 25° C. for about 24 hours. The reaction mixture was then cooled to 0to 5° C. and stirred for 3 hours. The solid material obtained wasfiltered, washed with 15 mL of cold ethanol, and dried under vacuum at35° C. Yield=90%.

EXAMPLE 8

Preparation of Hydralazine Hydrochloride

Hydralazine free base 45 g (prepared by the process of example 7A) wasdissolved in 1125 mL of methanol, 5 g activated carbon was added, andthe mixture stirred for about 30 minutes. The carbon was removed byfiltration and the clear filtrate was collected and then purged with HClgas for about 15 minutes. The resultant reaction mass is cooled to 0 to5° C., the precipitated off-white hydralazine hydrochloride wasfiltered, and then washed with cold methanol.

EXAMPLE 9A

Purification of Hydralazine Hydrochloride

Hydralazine hydrochloride wet material obtained by the process ofExample 8 was suspended in 400 mL methanol. Then 40 mL of triethylaminewas added and the temperature was raised to about 60 to 65° C. to get aclear solution; the hot solution was filtered to remove insolublematter, if any. Hydrogen chloride gas was purged through thesolution/filtrate to reach a pH of 2 to 4. The slurry mass was cooled toabout 0 to 5° C., stirred for about 1 hour, filtered, washed with 80 mLof cold methanol to isolate purified hydralazine hydrochloride, anddried under vacuum at 45° C. for about 3 hours. The dried material wassuspended in 370 mL of water and the temperature was raised to about 75to 80° C. to get a clear solution. About 3.7 g of activated carbon and0.5 g of EDTA were added, and the solution stirred for about 30 minutesat 75 to 80° C. The carbon was filtered from the hot solution, about 450mL of methanol was added, and the solution was cooled to 0 to 5° C. Thecold mixture was further cooled to about −20° C. From the resultingsolid, pure hydralazine hydrochloride was obtained by filtering, washingwith cold methanol, and drying under vacuum. A white precipitate ofhydralazine hydrochloride obtained was analyzed by HPLC for impuritiesand hydrazine content with following results: hydrazinecontent=0.00004%; yield about 95%.

EXAMPLE 9B

Purification of Hydralazine Hydrochloride

Hydralazine hydrochloride wet material obtained by the process ofExample 8 was suspended in 370 mL of water and the temperature wasraised to about 75 to 80° C. to get a clear solution. About 17 g ofactivated carbon and 0.5 g of EDTA were added, and the solution stirredfor about 30minutes at 75° to 80° C. The carbon was filtered from thehot solution, about 450 mL of methanol was added, the solution cooled toroom temperature. The pH of the solution was adjusted with dilute sodiumhydroxide solution to about 3 to 4.5 and the solution was then cooled to0° to 5° C. The cold mixture was further cooled to about −20° C. Fromthe resulting solid, pure hydralazine hydrochloride was obtained byfiltering, washing with cold methanol, and finally drying under vacuum.The dried white precipitate of hydralazine hydrochloride obtained wasanalyzed by RPLC for impurities and hydrazine content: hydrazinecontent=0.00004%; yield about 95%.

EXAMPLE 9C

Purification of Hydralazine Hydrochloride

Hydralazine hydrochloride wet material obtained by the process ofExample 8 was suspended in 370 mL of water and the temperature wasraised to about 75 to 80° C. to get a clear solution. About 3.7 g ofactivated carbon and 0.5 g of EDTA were added, and the solution stirredfor about 30 minutes at 75 to 80° C. The carbon was filtered from thehot solution, about 450 mL of methanol was added, and the solutioncooled to room temperature. pH of the solution was adjusted with sodiumbicarbonate to about 3 to 4.5 and the solution was cooled to 0 to 5° C.The cold mixture was further cooled to about −20° C. From the resultingsolid, pure hydralazine hydrochloride was obtained by filtering, washingwith cold methanol, and drying under vacuum. A white precipitate ofhydralazine hydrochloride obtained was analyzed by 1-1 PLC forimpurities and hydrazine content: hydrazine content=0.00004%; yieldabout 95%.

The foregoing description is meant to be illustrative and not limiting.Various changes, modifications, and additions may become apparent to theskilled artisan upon a perusal of this specification, and such are meantto be within the scope and spirit of the invention as defined by theclaims.

1. A process of purifying hydralazine hydrochloride comprising the stepsof: (a) performing a temperature-assisted dissolution of hydralazinehydrochloride in an aqueous solvent; (b) treating the solution with aclarifying agent selected from chelating agents, activated carbon, andmixtures thereof; (c) removing the clarifying agents by filtration andoptionally adjusting the pH of the filtrate with acid or base to about 2to 5; and (d) precipitating hydralazine hydrochloride from the filtrateby cooling, wherein the hydrazine content is reduced to a level of below0.001%.
 2. The process of claim 1, wherein the step of precipitatinghydralazine hydrochloride occurs in water.
 3. The process of claim 1,wherein the step of precipitating hydralazine hydrochloride occurs in anaqueous solvent mixture containing one or more water miscible organicsolvents.
 4. The process of claim 3, wherein the water miscible organicsolvent is a lower alkyl alcohol, tetrahydrofuran, acetonitrile, or amixture thereof.
 5. The process of claim 4, wherein the alcohol isselected from the group consisting of methanol, ethanol, isopropanol,and mixtures thereof.
 6. The process of claim 1, wherein the aqueoussolvent in step (a) is water.
 7. The process of claim 1, wherein theaqueous solvent in step (a) is an aqueous solvent mixture containing oneor more water miscible organic solvents.
 8. The process of claim 1,wherein the base is an amine, a hydroxide, a carbonate, a bicarbonate,or a mixture thereof.
 9. The process of claim 8, wherein the amine is analkyl amine selected from the group consisting of triethylamine,diethylamine, diisopropylamine, diisopropylethylamine, piperidine,alkylpiperidines and mixtures thereof.
 10. The process of claim 8,wherein the amine is an alkyl aryl amine selected from the groupconsisting of N-alkylanilines, pyridines, and mixtures thereof.
 11. Theprocess of claim 8, wherein the hydroxide is sodium hydroxide, potassiumhydroxide, lithium hydroxide, tetraalkylammonium hydroxide, or a mixturethereof.
 12. The process of claim 8, wherein the bicarbonate orcarbonate is a salt of sodium or potassium or a mixture thereof.
 13. Theprocess of claim 1, wherein the acid in step (c) is hydrochloric acid.14. The process of claim 1, wherein the chelating agent contains atleast one carboxyl functional group.
 15. The process of claim 14,wherein the chelating agent is ethylenediamine tetraacetic acid (ETDA),ethylene glycol-bis-(beta-amino-ethylether) N,N,N′,N′-tetraacetic acid(EGTA), cyclohexane-1,2-diaminetetraacetic acid (CDTA), or a mixturethereof.